CLINICAL EXPERIENCES WITH DESMOPRESSIN FOR LONG-TERM TREATMENT OF NOCTURIA

0022-5347/04/1723-1021/0 THE JOURNAL OF UROLOGY® Copyright © 2004 by AMERICAN UROLOGICAL ASSOCIATION

Vol. 172, 1021–1025, September 2004 Printed in U.S.A.

DOI: 10.1097/01.ju.0000136203.76320.f6

CLINICAL EXPERIENCES WITH DESMOPRESSIN FOR LONG-TERM TREATMENT OF NOCTURIA G. LOSE,*, † A. MATTIASSON, S. WALTER, O. LALOS, P. AND R. FREEMAN

VAN

KERREBROECK, P. ABRAMS

From the Department of Gynaecology, Glostrup Hospital (GL), Glostrup and Department of Urology, Odense University Hospital (SW), Odense C, Denmark, Department of Urology, Lund University Hospital (AM), Lund and Department of Obstetrics and Gynecology, University Hospital Norrland (OL), Umeå, Sweden, Department of Urology, University Hospital Maastricht (PvK), Maastricht, The Netherlands, and Southmead Hospital, Bristol Urological Institute (PA), Bristol and Derriford Hospital (RF), Plymouth, United Kingdom

ABSTRACT

Purpose: To our knowledge we report the first long-term use of desmopressin for nocturia. Patients previously responding to desmopressin in short-term studies were enrolled in this long-term open label study. Materials and Methods: Patients received treatment for 10 or 12 months with the optimal desmopressin dose (0.1, 0.2 or 0.4 mg orally at bedtime). Patients were followed a further month without treatment. Of the patients completing the short-term study 132 males (92%) and 117 females (83%) were recruited, and 95 (72%) and 87 (75%), respectively, completed long-term treatment. Results: The mean number of nocturnal voids was decreased in males and females throughout the study (1.3 to 1.6 and 1.2 to 1.3) compared with baseline (3.1 and 2.9, respectively). After followup the number of voids increased after treatment cessation. From baseline to 12 months the mean duration of the first sleep period gradually increased in males (157 to 288 minutes) and females (142 to 310 minutes). After followup the mean duration of the first sleep period decreased, confirming that it was a treatment related benefit. Desmopressin was well tolerated with few males (14%) or females (10%) withdrawing due to adverse events. Most adverse events were mild (44%) or moderate (44%) in severity. Four males experienced serious drug related adverse events, namely dizziness in 1, cardiac failure, headache and vomiting in 2, and chest pain and hypertension in 1. A female experienced 4 serious drug related adverse events, that is hyponatremia, headache, nausea and vertigo. Two patients had clinically significant hyponatremia. Conclusions: This long-term study shows that desmopressin is a generally well tolerated and effective treatment for nocturia. KEY WORDS: urinary tract, desmopressin, sleep, urination disorders, polyuria

Nocturia is a common condition experienced by all ages, particularly elderly individuals. Existing data indicate that 37.5 million Europeans experience nocturia.1 However, the absolute prevalence is under reported because individuals often do not consult physicians due to embarrassment or they believe that it is a normal part of aging.2 Nocturia is equally prevalent in men and women, and it increases with age.3, 4 It is not a trivial complaint and it can affect several aspects of patient health5 with detrimental effects on quality of life,6 sleep patterns,7 and increased morbidity and mortality.8 Nocturia is increasingly recognized as a condition in its own right with a multifactorial etiology. Nocturnal polyuria (overproduction of urine at night) is considered among the primary causes of nocturia,9, 10 responsible for up to 70% of cases.3, 11 Nocturia may also be caused by changes in fluid metabolism with subsequent high nocturnal urine production.12, 13 During the night serum levels of the antidiuretic hormone arginine vasopressin (AVP) increase and urine production decreases, minimizing the need to wake to void. It is believed that a proportion of patients with nocturia lack this increased production of AVP.10, 12 In addition, the increase in

nocturnal AVP can be decreased due to aging, so that daytime and nighttime AVP levels become similar.12 Desmopressin is a synthetic analogue of the pituitary hormone 8-arginine vasopressin. It acts as an antidiuretic agent by increasing water resorption in the distal and collecting tubules of the kidney. Earlier short-term studies (3 weeks) of desmopressin in nocturia showed it to be safe and effective in males and females.14, 15 In this study we evaluated long-term safety and efficacy in a 10 to 12-month period in patients successfully treated in the short-term study. To our knowledge this is the first time that desmopressin has been assessed for long-term nocturia treatment. METHODOLOGY

Design. In this open label, phase III, multinational extension study we evaluated the long-term safety and efficacy of desmopressin in males and females with nocturia. Patients had already received desmopressin in a short-term doubleblind study (3 weeks). Patients then received desmopressin for a further 10 or 12 months with the optimal dose (0.1, 0.2 or 0.4 mg orally at bedtime) found during dose titration in the short-term study. After treatment patients were followed a further month (month 11 or 13) to provide data on symptom reversibility. Patients were advised to urinate just before going to bed and not to drink more than sufficient to satisfy thirst from 1

Accepted for publication April 2, 2004. * Correspondence: Department of Gynecology, Glostrup Hospital, Nordre Ringvej, DK-2600 Glostrup, Denmark (telephone: ⫹45 4323 2842; FAX: ⫹45 4323 3974; e-mail: [email protected]). † Financial interest and/or other relationship with Ferring. 1021

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DESMOPRESSIN AS LONG-TERM NOCTURIA TREATMENT

hour before bedtime until 8 hours after drug intake. They were also instructed to avoid drinking liquids with a diuretic effect at night (eg caffeine and alcohol). Patients were required to attend the study center at visit 1 (final visit in the short-term study), and after 1, 4, 7, 10 and 12 months of treatment. The last clinic visit was 1 month after treatment cessation. In the week prior to each visit patients were required to maintain a diary in which they recorded the date, time of medication intake, any nocturnal micturitions, and the time of going to bed and rising in the morning. Primary and secondary end points. The primary objective was to assess the safety of long-term desmopressin treatment in patients with nocturia who responded during a short-term study. Particular emphasis was given to measuring serum sodium. The secondary objective was to evaluate long-term efficacy by assessing the number of nocturnal voids, time from bedtime to the first nocturnal void, nighttime duration (time from bedtime until rising in the morning) and the proportion responding (50% or greater decrease in the number of nocturnal voids compared with baseline). In addition, quality of life (patient bother score) was assessed after 4, 7, 10 and 12 months of treatment using the scoring system of the abbreviated International Continence Society (ICS)male16 or Bristol Female lower urinary tract symptoms (LUTS) questionnaires.17 The ICSmale questionnaire includes 26 questions on urinary symptoms occurrence (voiding symptoms, storage symptoms, post-micturition dribble and acute retention) and their effect on quality of life. The Bristol Female LUTS questionnaire includes 34 questions on the frequency of urinary symptoms (frequency, urgency, incontinence and pain), sexual function and effect on quality of life. Analyses were performed in the safety population, which included all patients receiving at least 1 dose of medication in the long-term study. Inclusion and exclusion criteria. Males and females 18 years or older with nocturia who successfully completed the short-term study and who had provided written informed consent were enrolled. Nocturia was defined as an average of 2 or greater voids nightly with nocturia index scores greater than 1, defined as mean nocturnal volume divided by maximum voided volume, measured at any time.18 Patients were excluded if they had urge incontinence or another voiding dysfunction, had received treatment with drugs known or suspected to interact with desmopressin (eg diuretics, tricyclic antidepressants, indomethacin, carbamazepine or chlorpropamide), had uncontrolled hypertension, had evidence of clinically relevant cardiac failure, or planned to become or were pregnant. Safety assessments. Safety was assessed by the incidence of adverse events, concomitant medication, changes in vital signs, weight, biochemical and hematological values (hemoglobin, and serum alanine aminotransferase, aspartate aminotransferase, creatine kinase, sodium, potassium and creatinine), urinalysis (dipstick) and physical examination. Adverse events, vital signs, weight and serum sodium were determined at each clinic visit. Patients who experienced any signs of hyponatremia underwent a general assessment and serum sodium was measured. Blood and urine laboratory analysis, and physical examination were done twice during the study. Statistical methods. Statistical analyses were done elsewhere using SAS, version 8 for Windows (SAS Institute, Cary, North Carolina). A safety assessment was the primary aim. No formal statistical analysis was performed and data are presented in descriptive fashion with summary tables and graphic displays with time. Safety and efficacy were assessed by patient age and doses with time. Descriptive statistics were used to describe data from the abbreviated ICSmale/Bristol Female LUTS questionnaires as well as demographic and baseline characteristics. For

ICSmale questions were combined to 5 scores, namely frequency (scale 0 to 3), nocturia (scale 0 to 4), voiding symptoms (scale 0 to 20), incontinence symptoms (scale 0 to 24) and interference with life (scale 0 to 3).19 Quality of life data are presented as simple patient distributions by visit. Frequency tables were used to summarize the prevalence (proportion of patients) of each symptom and the degree of bother at each visit. Simple distributions are presented for each symptom occurrence and for bother scores at visits 1 to 5 for patients who reported that particular symptom. RESULTS

Patient population. Of the patients completing the shortterm study 132 of 143 males (92%) and 117 of 141 females (83%) were enrolled into long-term treatment and received at least 1 dose of desmopressin (249). Overall 95 males (72%) and 87 females (75%) completed the study, including 62 males (47%) and 8 females (7%) who completed 11 months and 33 males (25%) and 79 females (68%) who completed 13 months of treatment (table 1). At the start desmopressin (0.1, 0.2 or 0.4 mg) was administered to 18%, 35% and 47% of males, and 14%, 39% and 47% of females, respectively. Only 28 patients (16 males and 12 females) changed the dose. Table 2 lists patient characteristics. Males had an average of 3.1 nocturnal voids nightly and a mean nocturnal index of 2.1 at baseline. The most frequently reported concurrent medical condition was hypertension in 29 males (22%), while prostate disorders were recorded in 18 (14%). At baseline females had an average of 2.9 nocturnal voids and a nocturia index of 1.9. The 2 most frequently reported concurrent medical conditions were unspecified uterine disorders in 20 women (17%) and hypertension in 14 (12%). Overall 37 males (28%) and 30 females (26%) withdrew from long-term treatment, including 18 (14%) and 12 (10%) due to adverse events, 5 (4%) and 8 (7%) due to a lack of efficacy, 6 (5%) and 5 (4%) at their request, and 8 (6%) and 5 (4%) for other reasons, respectively. Treatment compliance was good with 115 males (87%) and 100 females (85%) ingesting at least 80% of the medication. Long-term safety. Desmopressin was well tolerated during long-term treatment. The frequency and type of adverse events was similar to those in short-term studies. Overall there was a total of 259 adverse events in 92 males (70%) and a total of 398 in 90 females (77%) (table 3). Table 3 lists the most frequent adverse events occurring in 5% or more of patients. The majority of adverse events were mild (43%) or moderate (46%) (table 4). Of the males 32 (24%) reported a total of 57 and 29 females (25%) reported a total of 59 adverse events considered drug related, mainly headache, peripheral edema and dizziness (table 4). The frequency of patients experiencing treatment related adverse events was similar at all 3 doses in females but it increased slightly in males at increasing doses. There was a relatively higher incidence of treatment related adverse events in patients 65 years or older (27% vs 21% in males and 41% vs 19% in females). Of the males 17 (13%) reported a total of 26 and 9 females (8%) reported a total of 16 serious adverse events. One event resulted in a nondrug related death (renal carcinoma in a male). The frequency of TABLE 1. Patient population No. Men (%) No. Women (%) Completed short-term study Included in long-term study Completed long-term treatment (mos): 11 13 Withdrawn Withdrawn due to adverse events

143 132 (92) 95 (72) 62 (47) 33 (25) 37 (28) 18 (14)

141 117 (83) 87 (75) 8 (7) 79 (68) 30 (26) 12 (10)

DESMOPRESSIN AS LONG-TERM NOCTURIA TREATMENT TABLE 2. Baseline patient characteristics Characteristic

Men

No. pts Age: Mean ⫾ SD Range Body mass index (kg/m/m): Mean ⫾ SD Range Nocturnal vol (ml): Mean ⫾ SD Range 24-Hr urine vol/kg body wt (ml): Mean ⫾ SD Range Max voided vol (ml): Mean ⫾ SD Range Nocturnal voids: Mean ⫾ SD Range Nocturia index: Mean ⫾ SD Range

Women

132

117

65 (10.2) 24–88

56 (13.3) 21–85

27 (3.7) 19–40

27 (5.0) 17–40

783 (289) 307–1,650

769 (249) 269–1,443

22.1 (7.0) 10.8–48.2

26.6 (7.4) 12.5–43.1

386 (126) 100–900

421 (124) 160–750

3.1 ⫾ 1.1 1.6–9.6

2.9 ⫾ 0.8 1.4–5.0

2.1 ⫾ 0.7 1.0–4.8

1.9 ⫾ 0.5 1.0–3.9

TABLE 3. Adverse events during long-term treatment Men Adverse Event

Exposed Total adverse events Adverse events in 5% of pts or less: Abdominal pain Accident and/or injury Arthralgia Back pain Bronchitis Dizziness Headache Hypertension Influenza-like symptoms Nausea Peripheral edema Upper respiratory tract infection Most frequent (2% or greater) adverse events related to study medication: Dizziness Headache Micturition frequency Nausea Peripheral edema Urinary tract infection

No. (%) 132 (100) 92 (70)

Women No. Events

No. (%)

No. Events

259

117 (100) 90 (77)

398

10 (9) 11 (9) 8 (7) 10 (9) 2 (2) 6 (5) 18 (15) 4 (3) 12 (10) 6 (5) 6 (5) 25 (21)

12 12 14 14 2 9 53 4 12 6 7 31

8 6 6 7 7 8 8 7 12 3 3 10

(6) (5) (5) (5) (5) (6) (6) (5) (9) (2) (2) (8)

9 6 7 8 9 9 9 8 15 3 3 11

6 6 2 3 3 1

(5) (5) (2) (2) (2) (1)

7 7 2 3 3 2

2 8 3 2 4 3

(2) (7) (3) (2) (3) (3)

2 17 3 2 4 3

serious adverse events was similar at all 3 doses. Four males experienced a total of 6 serious adverse events considered drug-treatment, namely dizziness in 1, cardiac failure, headache and vomiting in 2, and chest pain and hypertension in 1. One female experienced 4 serious adverse events, namely hyponatremia, headache, nausea and vertigo (not related). Of the 249 participants 30 (12%) (18 males and 12 females) withdrew due to 49 adverse events, including 26 in males and 23 in females (table 4). There were no clearly dose related differences in the number of patients withdrawing from treatment. Fluctuations in serum sodium were low and in most patients they were without clinical relevance. Overall 35 of 249 patients (14%) (21 males and 14 females) had hyponatremia, which was nonclinically relevant in 33. No action was taken. The majority of hyponatremia cases (33 of 35) were asymptomatic borderline hyponatremia (serum sodium below normal range but 130 mmol/l or greater). One male and 1 female had symptomatic class I hyponatremia (serum sodium 125 mmol/l or greater but less than 130 mmol/l). No patients had

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class II hyponatremia (serum sodium less than 125 mmol/l). There were no clear dose related differences in the incidence of hyponatremia, although patients 65 years or older were at greater risk. No overall clinical abnormalities or changes were noted on laboratory tests or urinalysis and no overall clinically significant changes in vital signs were observed during this study. Long-term efficacy. In males and females the decreased mean number of nocturnal voids during the short-term study was maintained and further decreased during long-term treatment. The number of nocturnal voids in males was 1.3 to 1.6 and in females it was 1.2 to 1.3 during long-term treatment (fig. 1). Of the males being assessed the number who showed a clinical response (50% or greater decrease in the number of voids compared with baseline) increased from 37% (28 of 75) at the start of long-term treatment to 52% (49 of 95) at 10 months and 67% (22 of 33) at 12 months. The corresponding values in females were 46% (26 of 56) at the start of the study, and 66% (56 of 85) and 67% (53 of 67) at 10 and 12 months, respectively. The number of patients withdrawing from treatment significantly affected the results. The benefit on the sleep period in the short-term study was maintained and gradually increased during long-term treatment (fig. 2). At 10 and 12 months the mean duration of the first sleep period was 281 and 288 minutes in males, and 307 and 310 minutes in females, respectively (fig. 2). There was little change in the nighttime duration (8 to 9 hours) during the study in males or females. There was no indication of any dose related differences in efficacy. No clear age related differences were observed for the decrease in the number of voids, the duration of first sleep period or the proportion of responders, although males older than 65 years had a lower response rate than males younger than 65 years (63% vs 71% at 10 months). After the 1-month followup the number of nocturnal voids increased and the number of patients showing a clinical response decreased, indicating that treatment cessation was associated with an increase in nocturnal voids and a decrease in efficacy (fig. 1). Likewise, after followup the mean duration of the first sleep period decreased, confirming that increased sleep is a real treatment related benefit (fig. 2). Using the ICSmale and Bristol Female LUTS questionnaires the proportion of patients with nocturia as the most bothersome symptom decreased by greater than 50% during long-term treatment (table 5). Overall the ICSmale questionnaire revealed an improvement in quality of life with the voiding, nocturia problem and interference with life scores decreased at each visit compared with baseline. For example, the mean nocturia problem score (scale 0 to 4) at baseline was 2.9 and 2.2 at the treatment start, which then decreased to 1.5 after 10 to 12 months. DISCUSSION

The majority of patients (87.7%) completing the short-term studies were enrolled for long-term treatment. This suggests a high degree of patient acceptability of desmopressin treatment for nocturia. In this select group of desmopressin responders with nocturia and a polyuric background long-term desmopressin therapy was well tolerated. Overall adverse events were relatively infrequent and mild at all ages and consistent with those observed in short-term studies. Hyponatremia is considered significant side effect of desmopressin and 2 patients had clinically significant class I hyponatremia during the long-term studies. No patients had class II hyponatremia. Fluctuations in serum sodium were low and in most patients they were transient and without clinical relevance. Examination of individual data suggests that patients at highest risk for hyponatremia were those 65 years or older. The risk

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DESMOPRESSIN AS LONG-TERM NOCTURIA TREATMENT TABLE 4. Patients reporting mild, moderate or severe adverse events and adverse events during long-term treatment

No. (%)

No. Events

Total No. Events (%)

64 (55) 67 (57) 20 (17)

162 193 43

288 (43) 297 (46) 82 (12)

9 (8) 0 12 (10) 29 (25)

16 0 23 59

Men

Women

Adverse Event No. (%)

No. Events

Mild 60 (45) 126 Moderate 56 (42) 94 Severe 25 (19) 39 Long-term treatment: Serious 17 (13) 26 Death* 1 (1) 1 Leading to withdrawal 18 (14) 26 Related to study medication 32 (24) 57 * Patient died of renal carcinoma and death was not related to treatment.

FIG. 1. Mean number of nocturnal voids ⫹SD in male and female patients by treatment period. Values above bars indicate number of patients.

Long-term efficacy results reflect those in short-term studies. The significant decrease in the number of nighttime voids and subsequent increase in the first sleep period was maintained and in some cases even improved during long-term desmopressin treatment. Subgroup analysis revealed that efficacy results were similar across all doses and there were no clear differences among ages. However, it must be noted that some improvements in efficacy may have been due to patients withdrawing from treatment. Following treatment completion there was a decrease in all efficacy end points. This confirms that the decrease in the number of voids, an increase in the sleep period and an increase in the response proportion were real treatment benefits. Patients with nocturia could benefit from maintenance treatment with desmopressin, providing that serum sodium is assessed on a regular basis (every 6 months, or for suspected water intoxification or treatment related symptoms). The impact of nocturia on quality of life is important. Nocturia is a common cause of sleep disturbance. This is a particular problem in the elderly population because waking at night to go to the toilet increases the risk of falling.20 In this study there was a rapid decrease in the percent of patients bothered by nocturia and quality of life scores improved throughout treatment. CONCLUSIONS

Desmopressin was an effective treatment for nocturia, adding to patient quality of life. It was well tolerated but should be used with caution in people 65 years or older. The efficacy seen in short-term studies was maintained and even improved during long-term treatment. FIG. 2. Mean duration of first sleep period ⫹SD in male and female patients by treatment period. Values above bars indicate number of patients.

Statistical analyses were done at Ferring Pharmaceuticals AS. REFERENCES

TABLE 5. Patients with nocturia as most bothersome urinary symptom at baseline and during treatment Time Baseline Long-term study start 10 Mos 12 Mos

No./Total No. (%) Men

Women

80/132 (70) 29/75 (56) 26/102 (35) 7/33 (33)

85/117 (79) 39/61 (68) 19/93 (30) 18/79 (31)

of hyponatremia did not increase with treatment duration. Therefore, special precautions with regular monitoring of serum sodium, especially before, after initiation and after a dose increase, are recommended when treating elderly patients. Elderly patients should also be cautioned to ingest only enough fluid to satisfy thirst. Safety in this study compared to 30 years of clinical experience with desmopressin revealed no new concerns. Desmopressin had a favorable safety profile for the long-term treatment of nocturia at all doses.

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